Project Summary/Abstract Cannabis is the most commonly used illicit drug globally. The current trends indicate an increase in consumption of Cannabis-derived products for medicinal and recreational effects, prompted in part by increased legalization. Inhalation of Cannabis results in greater incidences of rhinitis, cough, wheeze and dyspnea. In some cases, exposure to Cannabis may be detrimental to pulmonary function and may exacerbate underlying asthma. Recent reports also emphasize a progressive escalation in incidences of allergic sensitization to Cannabis. However, the specific allergens associated with allergy to Cannabis remain poorly characterized. Current efforts into all research of Cannabis have been impeded due to the practical challenges in studying Schedule I substances. Consequently, a systematic and comprehensive evaluation of the allergenic profile that contributes towards sensitization to Cannabis allergens remains unfulfilled. Collectively, these factors have impeded the ability of physicians to accurately diagnose and treat Cannabis-related hypersensitivity reactions. In the current application, we propose to establish the role of atopy in Cannabis hypersensitivity (Aim 1) and examine the regional differences in sensitization to cross-reactive LTP from Cannabis and investigate the relevance of RuBisCO to Cannabis sensitization (Aim 2). To address these aims, we have formed a strong team of national and international basic science researchers and clinicians who are at the forefront of the Cannabis allergy field. Specifically, we propose to detail the Cannabis-specific IgE profile of 125 Cannabis hypersensitive subjects. We will also execute studies to clarify the relevance of two allergens (lipid transfer protein and RuBisCO enzyme) to Cannabis allergies. We will discuss our experimental findings in context of the clinical examination data collected from the subjects to draw objective conclusions. The findings from this study will form the basis for future basic science and clinical hypothesis-driven research. Our hope is to establish the clinical profiles of Cannabis nave and sensitized subpopulations and develop novel, standardized methodologies for evaluating Cannabis allergy so as to provide a pathway to improved diagnosis and evidence-based treatment of Cannabis allergy.